The IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, we discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. We reported in 1995 that mutations of the gc-associated kinase, JAK3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Related to IL-21, we previously cloned the IL-21 receptor, generated IL-21 transgenic mice and IL-21R knockout mice, elucidated the mechanism of IL-21 signaling, showed that IL-21 drives the differentiation of Th17 cells (which are important in pathological processes such as Crohn's disease), and critically regulates immunoglobulin production. A range of data also implicated IL-21 as serving a possible role in autoimmunity, particularly in lupus, with elevated IL-21 levels in the BXSB-Yaa mouse model of lupus. Moreover, prior studies from the lab indicated the possible utility of IL-21 as an anti-tumor agent. We previously showed that IL-21 plays a critical role in autoimmune diabetes, and during 2009, in a collaboration with Derry Roopenian at the Jackson Lab, we demonstrated that IL-21 signaling is essential for the development of systemic lupus erythematosus in the BXSB-Yaa mouse model of SLE. We also analyzed the role of IL-21 related to the development of T follicular helper cells and Th17 cells. Given that IL-21 promotes Th17 differentiation, it was interesting that IL-17 producing gamma-delta T cells in the thymus are the major IL-17 producing cells in naive animals and that they develop via a TGFb1-dependent mechanism but are not dependent on IL-21. IL-6 is an inflammatory cytokine produced by antigen-presenting cells and induces plasma cell differentiation and antibody production. In collaborative studies, it was reported that IL-6 induces IL-21 production by naive and memorey CD4 T cells and that this production is required for normal antibody production in vitro as well as in vivo in an influenza virus model. Moreover, the effects of IL-6 and IL-21 are dependent on STAT3. We also found that IL-21 is a potent inducer of IL-10 and Th1 priming with IL-21 leads to the accumulation of cells with immunosuppressive effects. We also reported that IL-21 signaling is required for the maximum inudction of IL-10 by either IL-6 or IL-27. These findings have implications related to the pathophysiology and SLE and other IL-21-mediated autoimmune diseases. In another collaborative study, we have also learned that IL-21 is critical for graft versus host disease (GVHD) in a mouse model. These data suggest that IL-21 is an important regulator of GVHD and that blocking IL-21 could represent a novel therapeutic strategy for attenuating or preventing this problem associated with transplantation. Moreover, we demonstrated that IL-21 promotes GVHD through enhanced production of effector CD4 T cells. Finally, we analyzed the mechanism by which IL-21 regulates expression of the Prdm1 gene which encodes BLIMP1, a critical regulator of plasma cell differentiation. We found that it acts via a critical composite site that requires both STAT3 and IRF4. Moreover, using microarray and ChIP-Seq methodology, we demonstrate that these factors cooperate with each other in a more general well to globally regulate gene expression. We also implicated for the first time IRF4 in T follicular helper cell development. Overall, our studies help to improve our understanding of signaling by the gc family cytokine IL-21. Our findings clarify molecular mechanisms that are relevant to autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.